POS1439 DEREGULATION IN ADULT IGA VASCULITIS SKIN AS THE BASIS FOR THE DISCOVERY OF NOVEL SERUM BIOMARKERS
Authors: M. Bajželj, M. Hladnik, T. D. Toluay, S. Sodin-Šemrl, A. Hocevar, K. Lakota
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Immunoglobulin A vasculitis (IgAV) is a small vessel leukocytoclastic vasculitis, characterized by vascular IgA deposits, and a variable clinical presentation. While IgAV might be self-limiting with a complete recovery, the severe acute form of the disease with gastrointestinal tract (GIT) and renal involvement may lead to significant morbidity, especially in adults. A skin or renal biopsy is still the golden standard for diagnosis. Currently, clinically used markers for IgAV cannot predict patients at risk for severe renal involvement and GIT complications with long-term consequences and which patients will exhibit a mild and self-resolving course limited to skin. <h3>Objectives</h3> This study aimed to use deregulated biological processes in patients' skin to identify potential serum biomarkers in adult IgAV, enabling stratification of patients with different clinical presentation. <h3>Methods</h3> Skin biopsy samples were collected from treatment-naïve adult IgAV patients at the time of diagnostic procedure: 1) skin-limited disease (n=3), 2), IgAV with renal involvement (n=3), and age-/sex-matched HC (n=3). RNA was isolated and 100 bp paired-end sequenced using the Illumina HiSeq 4000 platform (25.9 to 30.8 million reads were obtained per sample). Reads were mapped with Salmon tool against the human transcriptome (Ensemble Release 104). Differentially-expressed genes (log2 fold change ≥ │1│, padj &lt; 0.05) were computed using the R package DESeq2. Potential serum biomarkers were measured in sera of 59 IgAV patients and 22 healthy controls by magnetic bead-based multiplex assay using the Luminex platform. Statistically significant differences between groups were determined by the Mann-Whitney U test (for 2 groups) and the Kruskal-Wallis test followed by Dunn's post-test for multiple comparisons (≥ 3 groups). Spearman's rank correlation was calculated to measure the correlation between parameters. <h3>Results</h3> Based on differentially-expressed genes and deregulated biological pathways in IgAV patients' skin, we identified adipokines (fatty acid binding protein 4 (FABP-4), adiponectin, leptin, serpin A12 and angiopoietin-like protein 4 (ANGPTL4)), extracellular matrix associated proteins (osteopontin and matrix metalloproteinase-1 (MMP1)) and acute phase protein lipopolysaccharide binding protein (LBP) that were measured in patients' sera. We detected significantly higher serum levels of FABP-4 (p &lt; 0.001), leptin (p = 0.002), ANGPTL4 (p &lt; 0.001), osteopontin (p &lt; 0.001), MMP1 (p = 0.007) and LBP (p &lt; 0.001) in adult IgAV patients, as compared with healthy controls. Most highly enriched biological pathways identified only in skin of IgAV patients with renal involvement were the Regulation of lipolysis in adipocytes (padj 9.066 x 10<sup>-4</sup>) and ECM-receptor interaction (padj = 4.2882 x 10<sup>-3</sup>). Among the top 30 most differentially-expressed genes identified specifically in the skin of IgAV patients with renal involvement were LBP, LEP, SPP1, ADIPOQ, HP and RBP4. Serum levels of adiponectin (p=0.0043) and FABP-4 (p=0.049) were significantly higher in patients with renal involvement as compared to those with gastrointestinal involvement. The level of adiponectin (p=0.018) was significantly higher in patients with skin-limited IgAV compared to patients with gastrointestinal involvement. LBP positively correlated with the levels of two already routinely measured acute-phase proteins, C-reactive protein (CRP) (correlation coefficient = 0.550, p &lt; 0.001) and serum amyloid A (SAA) (correlation coefficient = 0.545, p &lt; 0.001), established markers of inflammation. Among adipokines, the level of ANGPTL4 positively correlated with CRP (correlation coefficient = 0.514, p &lt; 0.001) and SAA (correlation coefficient = 0.528, p &lt; 0.001). <h3>Conclusion</h3> We identified novel biomarkers of deregulated lipid metabolism and inflammation in adult patients with IgAV that are associated with internal organ involvement. Further analysis of their involvement in disease pathogenesis is warranted. <h3> Acknowledgements</h3> We acknowledge.Slovenian Research Agency for funding National research program Systemic autoimmune diseases P3-0314. <h3>Disclosure of Interests</h3> None Declared.